title: A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy.
abstract: OBJECTIVE
  Mutations in the SACS gene are commonly associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a complex neurodegenerative disorder characterized by progressive degeneration of the cerebellum and spinal cord tracts. The aim of this study was to identify the genetic cause of the disease in an Italian family with spastic paraplegia and peripheral neuropathy.
  
  
  METHODS
  Affected subjects were subjected to a comprehensive neurological examination including electromyography and brain magnetic resonance imaging. Genetic studies included exclusion of known disease genes, genome-wide linkage analysis using high density single nucleotide polymorphism genotyping and candidate gene sequencing.
  
  
  RESULTS
  Molecular analyses revealed a novel missense mutation in the SACS gene (c.11,104A>G) occurring in a homozygous state in patients and absent in 700 Italian control chromosomes. The mutation led to the amino acid substitution p.Thr3702Ala in the sacsin protein, in a possible protein-protein interaction site of UBE3A binding domain.
  
  
  CONCLUSIONS
  This study broadens the genetic spectrum of SACS mutations and expands the clinical ARSACS phenotype suggesting that the SACS gene can be considered in patients with non-canonical ARSACS clinical presentations.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Gregianin
authors.forename: G
authors.initials: G
authors.lastname: Vazza
authors.forename: E
authors.initials: E
authors.lastname: Scaramel
authors.forename: F
authors.initials: F
authors.lastname: Boaretto
authors.forename: A
authors.initials: A
authors.lastname: Vettori
authors.forename: E
authors.initials: E
authors.lastname: Leonardi
authors.forename: S C E
authors.initials: SC
authors.lastname: Tosatto
authors.forename: R
authors.initials: R
authors.lastname: Manara
authors.forename: E
authors.initials: E
authors.lastname: Pegoraro
authors.forename: M L
authors.initials: ML
authors.lastname: Mostacciuolo
mesh_terms: D000328:Adult; D003241:Consanguinity; D006360:Heat-Shock Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009128:Muscle Spasticity / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010264:Paraplegia / Q000235:genetics*; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human
keywords: ARSACS; linkage analysis; mutation identification; peripheral neuropathy; spastic paraplegia